Whole exome sequencing of extreme morbid obesity patients: translational implications for obesity and related disorders

Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female child with severe early-onset obesity. Additionally, the teenager patient had hypopituitarism and hyperprolactinaemia. A comprehensive bioinformatics analysis found de novo and compound heterozygote sequence variants with a damaging effect on genes previously associated with obesity in mice (LRP2) and humans (UCP2), among other intriguing mutations affecting ciliary function (DNAAF1). A gene ontology and pathway analysis of genes harbouring mutations resulted in the significant identification of overrepresented pathways related to ATP/ITP (adenosine/inosine triphosphate) metabolism and, in general, to the regulation of lipid metabolism. We discuss the clinical and physiological consequences of these mutations and the importance of these findings for either the clinical assessment or eventual treatment of morbid obesity.Gilberto Paz-Filho, Margaret C.S. Boguszewski, Claudio A. Mastronardi, Hardip R. Patel, Angad S. Johar, Aaron Chuah, Gavin A. Huttley, Cesar L. Boguszewski, Ma-Li Wong, Mauricio Arcos-Burgos and Julio Licini

Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans

More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein α-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associ

STRP Screening Sets for the human genome at 5 cM density

BACKGROUND: Short tandem repeat polymorphisms (STRPs) are powerful tools for gene mapping and other applications. A STRP genome scan of 10 cM is usually adequate for mapping single gene disorders. However mapping studies involving genetically complex disorders and especially association (linkage disequilibrium) often require higher STRP density. RESULTS: We report the development of two separate 10 cM human STRP Screening Sets (Sets 12 and 52) which span all chromosomes. When combined, the two Sets contain a total of 782 STRPs, with average STRP spacing of 4.8 cM, average heterozygosity of 0.72, and total sex-average coverage of 3535 cM. The current Sets are comprised almost entirely of STRPs based on tri- and tetranucleotide repeats. We also report correction of primer sequences for many STRPs used in previous Screening Sets. Detailed information for the new Screening Sets is available from our web site: . CONCLUSION: Our new human STRP Screening Sets will improve the quality and cost effectiveness of genotyping for gene mapping and other applications

A codon substitution model that incorporates the effect of the GC contents, the gene density and the density of CpG islands of human chromosomes

Abstract Background Developing a model for codon substitutions is essential for the analyses of protein sequences. Recent studies on the mutation rates in the non-coding regions have shown that CpG mutation rates in the human genome are negatively correlated to the local GC content and to the densities of functional elements. This study aimed at understanding the effect of genomic features, namely, GC content, gene density, and frequency of CpG islands, on the rates of codon substitution in human chromosomes. Results Codon substitution rates of CpG to TpG mutations, TpG to CpG mutations, and non-CpG transitions and transversions in humans were estimated by comparing the coding regions of thousands of human and chimpanzee genes and inferring their ancestral sequences by using macaque genes as the outgroup. Since the genomic features are depending on each other, partial regression coefficients of these features were obtained. Conclusion The substitution rates of codons depend on gene densities of the chromosomes. Transcription-associated mutation is one such pressure. On the basis of these results, a model of codon substitutions that incorporates the effect of genomic features on codon substitution in human chromosomes was developed.</p

The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.M-L Wong, M Arcos-Burgos, S Liu, J I Vélez, C Yu, B T Baune, M C Jawahar, V Arolt, U Dannlowski, A Chuah, G A Huttley, R Fogarty, M D Lewis, S R Bornstein, and J Licini

Relationship between amino acid composition and gene expression in the mouse genome

<p>Abstract</p> <p>Background</p> <p>Codon bias is a phenomenon that refers to the differences in the frequencies of synonymous codons among different genes. In many organisms, natural selection is considered to be a cause of codon bias because codon usage in highly expressed genes is biased toward optimal codons. Methods have previously been developed to predict the expression level of genes from their nucleotide sequences, which is based on the observation that synonymous codon usage shows an overall bias toward a few codons called major codons. However, the relationship between codon bias and gene expression level, as proposed by the translation-selection model, is less evident in mammals.</p> <p>Findings</p> <p>We investigated the correlations between the expression levels of 1,182 mouse genes and amino acid composition, as well as between gene expression and codon preference. We found that a weak but significant correlation exists between gene expression levels and amino acid composition in mouse. In total, less than 10% of variation of expression levels is explained by amino acid components. We found the effect of codon preference on gene expression was weaker than the effect of amino acid composition, because no significant correlations were observed with respect to codon preference.</p> <p>Conclusion</p> <p>These results suggest that it is difficult to predict expression level from amino acid components or from codon bias in mouse.</p

The Embedding Problem for Markov Models of Nucleotide Substitution

10.1371/journal.pone.0069187PLoS ONE87-POLN